CN1268340C - Pharmaceutical composition containing fused indole compound - Google Patents

Abstract

Comprising N1-ⁿButyl-4-piperidinyl) methyl]-3, 4-dihydro-2H- [1, 3]* oxazino [3, 2-a]A pharmaceutical composition of an indole-10-carboxamide (SB 207266) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, wherein at least some of the SB 207266 or salt thereof is in granular form. Preferably, the composition further comprises a filler and/or a binder.

Description

Pharmaceutical composition containing fused indole compound

technical field

The present invention relates to a new composition containing SB 207266 or a pharmaceutically acceptable salt thereof, such as tablets or capsules thereof.

Background technique

WO 93/18036 (SmithKline Beecham) discloses a number of fused indole compounds such as 5-HT antagonists including, for example _, N-[1- ⁿ -butyl-4-piperidine as described in Example 3 on pages 17-18 base) methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxamide (SB 207266) or its preferred hydrochloride (SB 207266-A). These compounds have been disclosed for the treatment or prophylaxis of gastrointestinal, cardiovascular and CNS disorders, especially irritable bowel syndrome. WO 93/18036 also describes it in the usual terms on pages 6-7 of the specification: "Specific cardiac 5-HT receptor _antagonists for the prevention of 5-HT-associated atrial fibrillation and other arrhythmias May reduce the incidence of stroke." For compound SB 207266 see also US 5,852,014, EP 0 884 319 A2, LMGaster et al, "Journal of Medical Chemistry" (J.Med.Chem.), 1995, 38, 4760-4763 and Drugs of the Future, 1997, 22 (12 ), 1325-1332, which is highly selective for the 5HT ₄ receptor via the 5HT receptor. SB 207266 is structured as follows:

For an improved synthesis of SB 207266, see WO 98/07728, WO 98/11067; WO 00/03983; and WO 00/03984.

There are several methods disclosed in the art for the preparation of the free base form or the hydrochloride salt. Example 3 on pages 17-18 of WO 93/18035 discloses the preparation of SB 207266 in free base form according to methods 1 and 2. Method 2 also disclosed conversion to the hydrochloride salt and recrystallization from ethanol/60-80 volatile oil yielded a white solid. L. Gaster, Drugs of the Future, 1997, 22(12), 1325-1332 discloses a similar method for the formation of the HCL salt by treating the SB 207266 free base with anhydrous HCL in ethanol. WO 98/07728 discloses three novel processes for the preparation of free bases on page 6, line 5 to page 7, line 20. WO 98/07728 also discloses two methods for the preparation of HCl salts (SB 207266A)---method A on page 7, line 22 to page 8, line 9, and page 8, line 10 to page 8 Method B on line 19. On page 8, lines 10-19 of WO 98/07728, method B for the preparation of SB 207266 hydrochloride is as follows: "N-[(1-butyl-4-piperidinyl)methyl]-3,4 -Dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxamide (SB-207266) (100g, 0.27mol) was dissolved in ethanol (870ml), and filtered The resulting solution was removed to remove particulates. Anhydrous HCl in ethanol (83ml, 3.6M, 0.30mol) was added to precipitate the product from solution. The crystallization slurry was heated to redissolve the solids and hexane (550ml) was added. Cool to room temperature Afterwards, the mixture was cooled to 0-5 degrees and stirred at room temperature for about two hours. The solid was isolated by filtration and vacuum dried at about 40 degrees to obtain the product, N-[(1-butyl-4-piperidinyl )methyl]-3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxamide hydrochloride, yield 94% (102.8 g). "

Contents of the invention

Problems have been recognized with certain methods of preparing SB 207266 hydrochloride which are similar or identical to the method disclosed in method B on page 8, lines 10-19 of WO 98/07728, wherein the hydrochloride is dissolved in ethanol, industrial methylated spirits (IMS, e.g. _ethanol with about ₁ % A solvent of ₅ -C ₁₀ hydrocarbons (for example, hexane and/or heptane) allows crystallization.

A first aspect of the recently recognized problem is that these processes produce SB207266 hydrochloride in the form of very small particles. For example, the table below shows particle size data for several batches of SB-207266-A prepared by a method similar to method B on page 8 of WO 98/07728, but wherein heptane was used instead of hexane in the crystallization step:

batch DV90(μm) DV50(μm) DV10(μm) BDC-H-01C 12.8 5.3 1.4 BDC-G-02C 13.8 5.7 1.5 BDC-G-03C 16.4 6.8 1.8 BDC-G-04C 14.4 5.3 1.4 BDC-G-05C 14.6 5.8 1.5 average 14.4 5.8 1.5

DV 90, DV 50 and DV 10 indicate that 90%, 50% and 10% of the volume of the substance is smaller than the specified micron size, respectively.

A second aspect of the recently recognized problem is the discovery that SB 207266 hydrochloride produced by these methods is very viscous and has poor flowability/flow characteristics.

A third aspect of the recently recognized problem is that at the above concentrations in pharmaceutical formulations, this The viscous drug material makes the composition extremely immobile, making it difficult to form tablets or form capsules. It has been found that, for oral administration in humans, it contains SB-207266 hydrochloride (about 5.0 mg), microcrystalline cellulose (30.0 mg), mannitol (112.0 mg), magnesium stearate (3.0 mg), which A composition of SB 207266 with a total tablet weight of about 150 mg is possible to tablet. However, with this formulation, higher concentrations of SB-207266 hydrochloride are not readily tablettable.

A fourth aspect of the problem that has recently been recognized is that small particle SB207266 hydrochloride has a low bulk density, which increases with the addition of water. This means that hardly anything can be added in a fixed volume mixer, resulting in a very inefficient production method as the large volume equipment has to be used for relatively small volumes of drug (smaller plant throughput).

It has now been found that some or all of these problems can be at least partially overcome or reduced by forming the SB 207266 hydrochloride into particles having a particle size larger than that of the original SB 207266 hydrochloride, e.g. Granulation method. These granules have been found to have better flowability for the tableting process. It has also been found that the addition of fillers to the granules, especially insoluble fillers such as CaHPO ₄ and/or Ca ₃ (PO ₄ ) ₂ can help to form granules with pharmaceutically favorable properties, e.g. Dissolution of the very soluble SB 207266 hydrochloride is minimized, thus minimizing fusing of unwanted particles after solvent removal. It is also expected that all or some of these benefits are obtained in free bases which are believed to have generally small particle sizes, e.g., when hexane is crystallized in toluene solution, the free base passes through the filter very slowly (e.g., WO 98/ Method A on page 6, lines 19-23 of 07728 and method C on page 7, lines 14-20). We believe that other similar salts besides the hydrochloride are also beneficial.

Therefore, one aspect of the present invention provides a kind of N-[1- ⁿ -butyl-4-piperidinyl) methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2 -a] A pharmaceutical composition of indole-10-carboxamide (SB 207266) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, wherein at least some of SB 207266 or a salt thereof is in the form of granules , and said SB 207266 or a salt thereof accounts for at least 4wt.% of the weight of the composition in the composition.

The composition is preferably a tablet, or the composition of the invention may be a capsule containing the composition.

Preferably, the particles comprising SB 207266 or a salt thereof have a particle size defined by "D50", or expressed by weight (DM50) or volume (DV50) > 100 microns (microns), such as 100-1000 microns, more preferably > 200 microns, such as 200-1000 or 200-500 microns, more preferably ≥250 microns, such as 250-500 microns. Preferably, the particles comprising 50% by weight or volume of SB 207266 or a salt thereof have a particle size within the specified size range.

Preferably, the particles comprising SB 207266 or a salt thereof have a particle size defined by "D10", or expressed by a weight (DM10) or volume (DV10) > 10 microns (microns), such as 10-1000 microns, more preferably > 50 microns, such as 50-1000 or 50-500 microns, more preferably ≥100 microns, such as 100-500 microns.

Compositions of the present invention comprising particles having the above-mentioned medium to large particle sizes are generally less viscous, flow better and are therefore less prone to the above-mentioned formulation problems.

Preferably, the granules of SB 207266 or a salt thereof (e.g., before granulation and/or after granulation; e.g., in the granules) have a D50 defined by "D50" or expressed by weight (DM50) or volume (DV50). , a particle size of ≤ 80 microns (microns), more preferably ≤ 50 microns, further preferably ≤ 20 microns, even more preferably ≤ 10 microns, most preferably ≤ 8 microns. Preferably, 50% by weight or volume of the particles of SB 207266 or a salt thereof (e.g., before and/or after forming the particles; e.g., in the particles) have a particle size within the specified size range.

Preferably, the granules of SB 207266 or a salt thereof (e.g., before granulation and/or after granulation; e.g., in the granules) have a weight (DM10) or volume (DV10) defined by "D10" , a particle size of ≤ 20 microns (microns), more preferably ≤ 10 microns, further preferably ≤ 5 microns, even more preferably ≤ 2.5 microns, most preferably ≤ 2 microns. Preferably, 10% by weight or volume of the particles of SB 207266 or a salt thereof (e.g., before and/or after forming the particles; e.g., in the particles) have a particle size within the specified size range.

Preferably, the granules of SB 207266 or a salt thereof (e.g., before and/or after granulation; e.g., in the granules) have a D90 defined by "D90" or expressed by weight (DM90) or volume (DV90). , a particle size of ≤ 100 microns (microns), more preferably ≤ 50 microns, further preferably ≤ 20 microns. Preferably, 90% by weight or volume of the particles of SB 207266 or a salt thereof (e.g., before and/or after forming the particles; e.g., in the particles) have a particle size within the specified size range.

As stated above, SB 207266 or its salts with such a small particle size are most likely to cause the above problems and are most likely to benefit from the present invention.

In general, granule size (D50, D10, D90, etc.) can be determined by screening with one or more sieves (e.g., for granules prior to further processing into tablets, and/or for determining powders in capsules) . In the case of tablets, for example by sectioning the tablet (e.g., optically, by microscopy, or otherwise) - the diameter of particular particles can be estimated by methods that allow the particle size distribution to be estimated from volume, and thus from weight to measure.

Preferably, it is present in the composition at least 4 wt.%, or preferably at least 6 wt.%, or preferably at least 8 wt.% by weight of the composition. Preferably, at most 95 wt.% of SB 207266 or a salt thereof is present in the composition, more preferably at most 70 wt.%, most preferably at most 50 wt.%. For example, about 10-100 mg (for example, 10, 20, 25, 40, 50, 75, 80 and 100 mg) SB 207266 or a salt thereof is ideal.

Preferably, N-[1- ^n- butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10- The carboxamide (SB 207266) or a pharmaceutically acceptable salt thereof comprises, for example, is the hydrochloride salt of SB 207266 (SB207266-A).

Preferably, the granules containing SB 207266 or a salt thereof also contain a filler (diluent). Mixing the filler with SB 207266 or its salts prior to granulation generally aids granulation. Granulation of pure SB 207266 or its salts is difficult.

Preferably, the filler (diluent) has an abrasive action. This helps reduce the stickiness of SB 207266 or salt.

Preferably, the filler (diluent) is insoluble, almost insoluble, very slightly soluble or slightly soluble (more preferably insoluble or almost insoluble) in the/the granulation solvent such as water and/or ethanol. The terms "practically insoluble", "very slightly soluble" and/or "slightly soluble" may be as defined in the British Pharmacopoeia, the European Pharmacopoeia and/or the US Pharmacopoeia. "Practically insoluble" according to British Pharmacopoeia 1999 (p. 11) means that at least 10 liters of solvent are required to dissolve 1 gram of filler (eg at room temperature, eg 20 degrees or preferably 25 degrees). "Very slightly soluble" according to the British Pharmacopoeia means that at least 1-10 liters of solvent are required to dissolve 1 gram of filler (eg at 25 degrees). "Sparsely soluble" according to the British Pharmacopoeia means that at least 100 ml-1 liter of solvent is required to dissolve 1 gram of filler (eg at 25 degrees).

During (wet) granulation, almost insoluble, very slightly soluble or sparingly soluble (preferably insoluble) fillers often minimize/reduce unwanted agglomeration of granules after solvent removal, and/or Improve the quality of pellets.

Preferably, the filler comprises any pharmaceutically acceptable metal (eg calcium or magnesium) salt which is practically insoluble, very slightly soluble or slightly soluble (preferably insoluble) in granulation solvents such as water and/or ethanol.

Such salts may be, for example, phosphates, hydrogenphosphates, carbonates or bicarbonates. These insoluble to slightly soluble salts include calcium phosphate, dibasic calcium phosphate, calcium carbonate, magnesium carbonate, magnesium phosphate, and the like.

Preferably, the filler comprises dibasic calcium phosphate (ie dicalcium phosphate, CaHPO ₄ ), more preferably dibasic calcium phosphate hydrate, eg dihydrate (ie CaHPO ₄ ·2H ₂ O). Anhydrous dibasic calcium phosphate may also be used. CaHPO ₄ (eg, hydrated or anhydrous), has an abrasive action and helps reduce the cohesiveness of SB 207266 or its salts; it is insoluble in water, which facilitates the granulation process described above. Alternatively (or in addition), the filler may comprise calcium phosphate, tertiary calcium phosphate Ca ₃ (PO ₄ ) ₂ .

Preferably the filler comprises up to 95% by weight of the granules and/or up to 70% by weight of the composition. Preferably, the filler comprises > 15 wt % or > 20 wt % or > 30 wt % of the composition. Preferably, the weight ratio of filler to drug in the composition or granule is at least 1:3, preferably at least 1:2.5, or at least 1:2 or at least 2:3.

Preferably, the composition includes an excipient, such as microcrystalline cellulose (MCC), as a tableting and/or granulation aid, preferably at least 15% by weight of the composition, more preferably 15-30% by weight (e.g. about 20wt%). MCC helps plastic deformation when tableting. Such tableting and/or granulation aids may be located inside or outside the granules.

Preferably, the composition includes a binder such as hydroxypropylmethylcellulose (HPMC) (eg, a low viscosity HPMC such as Pharmacoat 603). The binder is preferably present in the granules. Other possible binders may include HPC, HEC, HMC, methylcellulose, ethylcellulose, and the like. Preferably, the binder may comprise about 2.5-10% by weight (eg, about 5% by weight) of the composition.

Preferably, the composition includes a disintegrant (eg, a tablet disintegrant) such as sodium starch glycolate. The disintegrant may preferably comprise about 2.5-10% by weight (eg about 5% by weight) of the composition.

Preferably, the composition includes a lubricant such as magnesium stearate. Preferably, the lubricant may comprise about 0.2-2% by weight (eg, about 1% by weight) of the composition.

The second aspect of the present invention is to provide a method for preparing N-[1- ^n- butyl-4-piperidinyl) methyl]-3,4-dihydro-2H-[1,3]oxazino[3 , 2-a] the method for the pharmaceutical composition of indole-10-carboxamide (SB 207266) or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers, wherein SB207266 or its salt account for at least 4% by weight of the composition.

The method comprises granulating at least some of SB 207266 or a salt thereof.

Preferably, the method further comprises mixing some or all of SB 207266 or a salt thereof with a filler and/or a binder prior to granulation. Fillers and/or binders are as defined above.

Preferably, the granules are formed in a granulation solvent (ie, using a "wet granulation" method), eg, the solvent includes or is water and/or ethanol, preferably water. After mixing SB 207266 or its salt with filler and/or binder, solvent can be added. It is preferred to use just enough solvent to enable granulation.

Preferably, the solvent is removed after particle formation, for example by drying.

Preferably, the composition/granules are then mixed optionally with other excipients and compressed into tablets.

SB 207266 or a salt thereof may be conveniently administered by any conventional route of administration, for example parenterally, orally, topically, by inhalation.

The steps of preparing the composition and/or tablets and/or capsules may comprise mixing, granulating and compressing or dissolving the components, depending on the desired formulation.

The excipient/carrier used in the present composition should be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The pharmaceutically acceptable carrier used can be, for example, solid or liquid. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time delay materials well known in the art, for example, glyceryl monostearate or glyceryl distearate alone or with a wax.

Various dosage forms can be employed. Thus, if a solid carrier is used, the preparation can be compressed into tablets, placed in a hard gelatine capsule in powder or granulated form or in the form of a troche or lozenge. The amount of solid carrier will vary widely, but preferably from about 25 mg to about 1 g. When liquid carriers are used, the preparations are in the form of syrups, emulsions, soft gelatin capsules, sterile injectable liquids such as ampoules or non-aqueous liquid suspensions.

Particularly preferred oral compositions of SB 207266 for oral administration to humans are as follows:

SB-207266 5.0mg Sodium starch glycolate 12.5mg

Microcrystalline Cellulose 50.0mg Dicalcium Phosphate 167.5mg

HPMC 12.5mg Magnesium Stearate 2.5mg

Tablet weight 250mg

HPMC = hydroxypropyl methylcellulose

The dosage in the composition can be easily increased up to 20 mg. The composition is obtained by granulation.

These and other compositions of SB 207266 suitable for oral administration are described in the Examples below.

As if fully set forth, each publication was specifically and individually indicated to be incorporated by reference herein, and all publications, including but not limited to patents and patent applications, cited in this specification are hereby incorporated by reference.

The present invention will now be described by the following examples, which are given by way of illustration only and should not be construed as limiting the scope of the invention.

Example

SB 207266---N-[1- ^n- butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole -10-carboxamide (SB 207266) was prepared using the synthesis method described in the introduction, i.e. as in one or more of WO 98/07728, WO 98/11067, WO 00/03983, and/or WO 00/03984 mentioned. For example, for SB 207266 hydrochloride see especially method B of WO 98/07728 page 8 lines 10-19 with slight variations as above.

Example 1, 2, 3, 3A, 4 and 5-SB 207266 pharmaceutical composition

Comparative Example 1

An oral composition of SB 207266 for oral administration to humans is as follows:

SB-207266 5.0mg mannitol 112.0mg

Microcrystalline Cellulose 30.0mg Magnesium Stearate 3.0mg

Tablet weight 150mg

This composition is not obtained according to the invention.

Example 2

The oral composition of SB 207266 according to a human oral administration of the present invention is as follows:

SB-207266 5.0mg

Microcrystalline Cellulose 50.0mg

HPMC (Hydroxypropyl Methyl Cellulose) 12.5mg

Sodium starch glycolate 12.5mg

Dicalcium Phosphate 167.5mg

Magnesium stearate 2.5mg

Tablet weight 250mg

The dosage in this composition can be easily increased up to 20 mg. The composition is obtained by granulation.

Example 3

The tablet of Example 2 can be varied by increasing the dose of SB 207266 from 5 mg to 20, 60, 75, 80 or 100 mg (as determined by free base) and thus reducing the amount of dicalcium phosphate while maintaining The weight of the 250mg tablet remains unchanged. The composition can use the free base of SB 207266 or its hydrochloride.

Example 3A

The compositions of Examples 2 and 3 may use either the free base of SB 207266 or its hydrochloride salt.

Example 410, 25, and 40 mg dosage strength (measured according to pure free base)

SB-207266-A tablet

Tablets containing 10, 25, and 40 mg (as determined by free base) of SB-207266 hydrochloride (SB 207266-A) were prepared according to the compositions in the table below.

Embodiment 4 composition composition Function Quantity (mg/tablet)

10mg/tablet weight 25mg/tablet weight 40mg/tablet weight Active Ingredient SB-207266-A Other Ingredients Microcrystalline Cellulose (as in Ph. Eur. or NF) Hydroxypropyl Methylcellulose (as in USP) (as in Pharmacoat 603) Sodium Starch Glycolate (as in NF or Ph. Eur.) Dicalcium Phosphate Dicalcium Phosphate Hydrate (Dicalcium Phosphate Dihydrate) (eg Ph. Eur. or USP) Magnesium Stearate (eg. Ph. Eur. or NF) Purified Water ^** (eg. Ph. Eur. or USP) Opadry White YS-1-7003 Purified Water ^{* *} Total tablet weight API tableting or granulation auxiliary binder binder disintegrant main diluent lubricant granulation solvent coating film 11.0 ^* 50.012.512.5161.52.5**6.25**256.25 27.5 ^* 50.012.512.5145.02.5**6.25**256.25 44.0 ^* 50.012.512.5128.52.5**6.25**256.25

^* Equivalent to 10, 25, 40mg of pure free base

^** Removed during preparation

The SB-207266-A tablets of Example 4 were packaged in high-density polyethylene (HDPE) bottles with child-resistant induction-seal plastic caps.

The formulation is wet granulated using an insoluble primary excipient, calcium hydrogen phosphate dihydrate (dicalcium phosphate). Dibasic calcium phosphate dihydrate and microcrystalline cellulose are the main diluents, with microcrystalline cellulose helping to disperse the granulation solvent and overall compressibility. The added binder is hydroxypropyl methylcellulose, and the granulation is carried out in a conventional mixing granulator. The granule mixture is dried, sieved and blended with sodium starch glycolate as a disintegrant and magnesium stearate as a lubricant to form a tableting mixture. Tablets, which may be oval or round, are made on a suitable rotary tablet press.

Embodiment 4-detailed production process, inter-process control, and assembly processing procedure

Mix together SB-207266-A, microcrystalline cellulose, dibasic calcium phosphate dihydrate, and hydroxypropyl methylcellulose. Purified water is added to the blended powder while mixing in a high shear mixer granulator. The granules are dried in a fluid bed drier and then transferred to a blender where they are blended with sodium starch glycolate and magnesium stearate. The lubricated blend is compressed into tablet cores using a rotary tablet press. The cores were film coated with an aqueous dispersion of Opadry White YS-1-7003.

step:

1.0 Granulation

1.1 Combine SB-207266, microcrystalline cellulose, hydroxypropyl methylcellulose and dibasic calcium phosphate dihydrate in a suitable high shear mixer granulator.

1.2 Add purified water for granulation.

1.3 Dry the granules in a fluid bed dryer.

1.4 Using a suitable grinder, pass the dried granules through a stainless steel screen.

1.5 Determine the yield of pellets.

2.0 Manufacture of compressed mixtures

2.1 Mix the required amount of sodium starch glycolate and magnesium stearate with the dry granules.

2.2 Determine the yield of the compressed mixture.

3.0 tablet

3.1 Transfer the compression mixture to a suitable tablet machine.

3.2 Tablets

3.3 Determine the yield of the compressed tablets.

4.0 coating film

4.1 Move the tablet core to a suitable film coater.

4.2 Spin the core and spray on the Opadry's aqueous dispersion.

4.3 Randomly take factory test samples from the batch and mark them appropriately.

5.0 Bottling

5.1 Fill the appropriate amount of tablets into HDPE bottles which are induction sealed and have child resistant caps using suitable automated equipment.

Example 5

In a modification of Example 4, formulations containing 20 mg, 50 mg, 75 mg, 80 mg, and 100 mg of SB-207266 (used as the hydrochloride, but given doses based on free base determination) can be used for tableting. These formulations maintain (a) a total coated tablet weight of 256.25 mg, (b) a total uncoated tablet weight of 250 mg and (c) the amounts of other excipients in Example 4, but amount according to SB 207266 The change adjusts the amount of dibasic calcium phosphate dihydrate. These tablets can be round or oval.

Claims (92)

1. A kind of N-[1- ^n- butyl-4-piperidinyl) methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole -10-carboxamide, which is a pharmaceutical composition of SB 207266, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, wherein at least some of SB 207266 or a salt thereof is in the form of granules, and SB 207266 or a salt thereof in which the composition constitutes at least 4% by weight of the composition, The granules containing SB 207266 or a salt thereof further contain a filler which is a pharmaceutically acceptable salt of calcium or magnesium, phosphate, hydrogen phosphate, carbonate or bicarbonate, which is dissolved in water and/or Or insoluble in ethanol, almost insoluble, very slightly soluble or slightly soluble, And wherein the weight ratio of calcium or magnesium salt filler to SB 207266 or its salt in the granules is at least 1:3. 2. The pharmaceutical composition according to claim 1, wherein said particles comprising SB 207266 or a salt thereof have a particle size > 100 microns defined by "D50" expressed by weight or volume. 3. The pharmaceutical composition according to claim 1, wherein said particles comprising SB 207266 or a salt thereof have a particle size defined by "D50" expressed by weight or volume of 100-1000 microns. 4. The pharmaceutical composition according to claim 1, wherein said particles comprising SB 207266 or a salt thereof have a particle size defined by "D10" expressed by weight or volume > 10 microns. 5. The pharmaceutical composition according to claim 2, wherein said particles comprising SB 207266 or a salt thereof have a particle size defined by "D10" expressed by weight or volume of 10-1000 microns. 6. The pharmaceutical composition according to claim 3, wherein said particles comprising SB 207266 or a salt thereof have a particle size defined by "D10" expressed by weight or volume of 50-500 microns. 7. The pharmaceutical composition according to claim 1, wherein the particles of SB 207266 or a salt thereof have a particle size defined by "D50" expressed by weight or volume < 80 microns. 8. The pharmaceutical composition according to claim 2, wherein the particles of SB 207266 or a salt thereof have a particle size defined by "D50" expressed by weight or volume < 50 microns. 9. The pharmaceutical composition according to claim 7, wherein the particles of SB 207266 or a salt thereof have a particle size < 10 microns defined by "D10" expressed by weight or volume. 10. The pharmaceutical composition according to claim 8, wherein the particles of SB 207266 or a salt thereof have a particle size defined by "D90" or DV90 or DM90≤100 microns. 11. The pharmaceutical composition according to claim 8, wherein the particles of SB 207266 or a salt thereof in the particles have the particle size defined in claim 8. 12. The pharmaceutical composition according to claim 1, wherein SB 207266 or a salt thereof comprises the hydrochloride of SB 207266. 13. The pharmaceutical composition according to claim 7, wherein SB 207266 or a salt thereof comprises the hydrochloride of SB 207266. 14. The pharmaceutical composition according to claim 12, wherein the hydrochloride of SB 207266 is in a form that can be prepared by dissolving the hydrochloride in ethanol or industrial methylated alcohol, and adding C ₅ - C ₁₀ hydrocarbons and/or solvents containing C ₅ -C ₁₀ hydrocarbons allow crystallization. 15. The pharmaceutical composition according to claim 12, wherein the hydrochloride of SB 207266 has been prepared by dissolving the hydrochloride in ethanol or industrial methylated alcohol, and adding C ₅ -C ₁₀ Hydrocarbons and/or solvents containing C ₅ -C ₁₀ hydrocarbons for crystallization. 16. The pharmaceutical composition according to claim 14, wherein C ₅ -C ₁₀ hydrocarbons and/or solvents containing C ₅ -C ₁₀ hydrocarbons are hexane and/or heptane and/or hexane and/or heptane alkane solvent. 17. The pharmaceutical composition according to claim 1, wherein SB 207266 or a salt thereof is in the form of granules. 18. The pharmaceutical composition according to claim 1, wherein SB 207266 or a salt thereof accounts for at least 6% by weight of the composition in the composition. 19. The pharmaceutical composition according to claim 7, wherein SB 207266 or a salt thereof accounts for at least 6% by weight of the composition in the composition. 20. The pharmaceutical composition according to claim 12, wherein SB 207266 or a salt thereof accounts for at least 6% by weight of the composition in the composition. 21. The pharmaceutical composition according to claim 18, wherein SB 207266 or a salt thereof accounts for up to 70% by weight of the composition in the composition. 22. The pharmaceutical composition according to claim 20, wherein SB 207266 or a salt thereof accounts for up to 50% by weight of the composition in the composition. 23. A composition according to any one of claims 1 to 22, wherein the calcium or magnesium salt filler has an abrasive effect. 24. A composition according to any one of claims 1 to 22, wherein the calcium or magnesium salt filler is insoluble or barely soluble in water and/or ethanol. 25. A composition according to any one of claims 1-22, wherein the calcium or magnesium salt filler is insoluble, practically insoluble, very slightly soluble or slightly soluble in water. 26. A composition according to claim 25, wherein the calcium or magnesium salt filler is insoluble, barely soluble in water. 27. The composition according to any one of claims 1 to 22, wherein the insoluble to slightly soluble pharmaceutically acceptable calcium or magnesium salt filler comprises Ca ₃ (PO ₄ ) ₂ , CaHPO ₄ , carbonic acid Calcium, Magnesium Carbonate or Magnesium Phosphate. 28. The composition according to claim 27, wherein the calcium or magnesium salt filler comprises _CaHPO4 and/or _Ca3 ( _PO4 ) ₂ . 29. The composition of claim 28, wherein the calcium or magnesium salt filler comprises _CaHPO4 . 30. The composition of claim 28, wherein the calcium or magnesium salt filler is _CaHPO4 . 31. _The composition of claim 29, wherein the calcium or magnesium salt filler comprises _CaHPO4-2H2O . 32. A composition as claimed in any one of claims 1 to 22 wherein the calcium or magnesium salt filler constitutes up to 95% by weight of the granule. 33. A composition as claimed in any one of claims 1 to 22 wherein the calcium or magnesium salt filler constitutes up to 70% by weight of the composition. 34. A composition according to any one of claims 1 to 22, wherein calcium or magnesium salt fillers constitute > 15% by weight of the composition. 35. The composition of claim 28, wherein the calcium or magnesium salt filler comprises > 15% by weight of the composition. 36. The composition according to any one of claims 1-22, wherein calcium salt or magnesium salt filler constitutes > 20% by weight of the composition. 37. A composition according to any one of claims 1 to 22, wherein the weight ratio of calcium salt or magnesium salt filler to SB 207266 or a salt thereof in the granules is at least 1:2. 38. The composition of claim 27, wherein the weight ratio of calcium or magnesium salt filler to SB 207266 or a salt thereof in the granules is at least 2:3. 39. A composition according to any one of claims 1 to 22, wherein the composition comprises microcrystalline cellulose as a tableting and/or granulation aid. 40. The composition according to claim 12, wherein the composition comprises microcrystalline cellulose as a tableting and/or granulation aid and present inside the granules. 41. A composition according to claim 35, wherein the composition comprises microcrystalline cellulose as a tableting and/or granulation aid and is present within the granules. 42. The composition of claim 39, wherein microcrystalline cellulose comprises at least 15% by weight of the composition. 43. The composition of claim 41, wherein microcrystalline cellulose comprises at least 15% by weight of the composition. 44. The composition of claim 42, wherein microcrystalline cellulose is present in the interior of the particles. 45. A composition according to any one of claims 1 to 22 which includes a binder. 46. The composition according to claim 45, wherein the binder is hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose or ethyl cellulose. 47. The composition of claim 45, wherein the binder is hydroxypropylmethylcellulose. 48. The composition according to claim 45, wherein the binder comprises 2.5-10 wt.% of the composition. 49. A composition according to any one of claims 1 to 22 which includes a disintegrant. 50. The composition according to claim 49, wherein the disintegrant comprises 2.5-10 wt.% by weight of the composition. 51. A composition according to any one of claims 1 to 22 which includes a lubricant. 52. The composition of claim 51, wherein the lubricant is magnesium stearate. 53. The composition according to claim 51, wherein the lubricant comprises 0.2-2 wt.% by weight of the composition. 54. A composition according to any one of claims 1 to 22 which is in the form of a tablet or contained within a capsule. 55. A composition according to any one of claims 1 to 22, wherein the granules are formed in a granulation solvent, ie using a "wet granulation" method. 56. The composition of claim 12, wherein the granules are formed in a granulation solvent, ie using a "wet granulation" method. 57. The composition of claim 28, wherein the granules are formed in a granulation solvent, ie using a "wet granulation" method. 58. The composition of claim 34, wherein the granules are formed in a granulation solvent, ie using a "wet granulation" method. 59. The composition of claim 55, wherein the granulation solvent comprises or is water and/or ethanol. 60. A preparation containing N-[1- ^n- butyl-4-piperidinyl)methyl]-3,4-dihydro-2H-[1,3]oxazino[3,2-a]ind Indole-10-carboxamide, which is SB 207266, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, the method of the pharmaceutical composition, and wherein SB 207266 or a salt thereof is contained in the composition Accounting for at least 4wt.% of the weight of the composition, The method comprises granulating at least some of SB 207266 or a salt thereof, The granules containing SB 207266 or a salt thereof further contain a filler which is a pharmaceutically acceptable salt of calcium or magnesium, phosphate, hydrogen phosphate, carbonate or bicarbonate, which is dissolved in water and/or Or insoluble in ethanol, almost insoluble, very slightly soluble or slightly soluble, wherein the weight ratio of calcium or magnesium salt filler to SB 207266 or its salts in the granules is at least 1:3, Wherein the method comprises mixing some or all of SB 207266 or a salt thereof with a calcium or magnesium salt filler prior to granulation. 61. The method of claim 60, wherein the granules are formed in a granulation solvent, ie using a "wet granulation" method. 62. The method of claim 61, wherein the granulation solvent comprises or is water and/or ethanol. 63. The method of claim 62, wherein the granulation solvent comprises or is water. 64. The method of claim 62, wherein the calcium or magnesium salt filler is insoluble, almost insoluble, very slightly soluble or slightly soluble in the granulation solvent used in the "wet granulation" process. 65. The method according to claim 61, wherein the granulation solvent is added after mixing SB 207266 or a salt thereof with a calcium or magnesium salt filler and optionally with a binder. 66. The method of claim 65 using just enough solvent to enable granulation. 67. The method of claim 61, wherein the solvent is removed after forming the particles. 68. The method of claim 67, wherein the solvent is removed by drying after forming the particles. 69. The method of claim 67, wherein the granules are then optionally mixed with other excipients and compressed into tablets. 70. The method of claim 61, wherein the calcium or magnesium salt filler comprises _CaHPO4 and/or _Ca3 ( _PO4 ) ₂ . 71. The method according to any one of claims 60-69, wherein the insoluble to slightly soluble pharmaceutically acceptable calcium or magnesium salt filler comprises _Ca3 ( _PO4 ) ₂ , _CaHPO4 , calcium carbonate , magnesium carbonate, or magnesium phosphate. 72. The method of claim 71, wherein the calcium or magnesium salt filler comprises _CaHPO4 and/or _Ca3 ( _PO4 ) ₂ . 73. A method according to any one of claims 60 to 69, wherein the calcium or magnesium salt filler comprises > 15% by weight of the composition. 74. The method of claim 73, wherein the insoluble to slightly soluble pharmaceutically acceptable calcium or magnesium salt filler comprises _Ca3 ( _PO4 ) ₂ , _CaHPO4 , calcium carbonate, magnesium carbonate, or phosphoric acid magnesium. 75. The method of claim 74, wherein the calcium or magnesium salt filler comprises _CaHPO4 and/or _Ca3 ( _PO4 ) ₂ . 76. The method of claim 71, wherein SB 207266 or a salt thereof comprises the hydrochloride salt of SB 207266. 77. The method of claim 72, wherein SB 207266 or a salt thereof comprises the hydrochloride salt of SB 207266. 78. The method of claim 73, wherein SB 207266 or a salt thereof comprises the hydrochloride salt of SB 207266. 79. The method of claim 74, wherein SB 207266 or a salt thereof comprises the hydrochloride salt of SB 207266. 80. The method of claim 75, wherein SB 207266 or a salt thereof comprises the hydrochloride salt of SB 207266. 81. The method of claim 61 comprising mixing some or all of SB207266 or a salt thereof with a binder prior to granulation. 82. The method of claim 81, wherein the binder comprises 2.5% to 10% by weight of the composition. 83. The method according to any one of claims 60-69 or claim 81, wherein the composition comprises microcrystalline cellulose as a tableting and/or granulation aid, and said microcrystalline cellulose is present inside the particle. 84. The method of claim 83, wherein microcrystalline cellulose comprises at least 15% by weight of the composition. 85. The method of claim 60, wherein the composition is as defined in any one of claims 2-22. 86. The method of claim 61, wherein the composition is as defined in any one of claims 2-22. 87. The method of claim 62, wherein the composition is as defined in any one of claims 2-22. 88. A pharmaceutical composition according to any one of claims 1-22, prepared by the method defined in claim 61. 89. A pharmaceutical composition according to any one of claims 1-22, prepared by the method of claim 62. 90. The pharmaceutical composition according to claim 88, wherein the calcium or magnesium salt filler comprises _CaHPO4 and/or _Ca3 ( _PO4 ) ₂ . 91. The pharmaceutical composition according to claim 88, wherein calcium salt or magnesium salt filler constitutes > 15% by weight of the composition. 92. The pharmaceutical composition according to claim 90, wherein calcium salt or magnesium salt filler constitutes > 15% by weight of the composition.